3.1 Systemically Administered Amifostine
The compound S-2-(3-aminopropylamino)ethyl dihydrogen phosphorothioate (also known as amifostine, ethiofos, Ethyol.RTM., NSC 296961, and WR-2721, and which will hereinafter be referred to as "amifostine") has been known for over thirty years, and was originally developed by the Walter Reed Institute of Research as an antiradiation agent (radioprotectant). In particular, amifostine was developed for military use against x-ray or nuclear radiation which may be encountered during military conflicts. Bulk amifostine and other aminoalkyl dihydrogen phosphorothioates, and methods to obtain them, are disclosed in U.S. Pat. No. 3,892,824, which is incorporated herein by reference.
In addition to its utility as a military antiradiation agent, amifostine has demonstrated excellent utility as a non-military radioprotectant and chemoprotectant when administered systemically prior to chemotherapy and/or radiation therapy. Amifostine acts to protect normal tissue again the adverse effects which accompany the use of radiochemical therapies for the treatment of various cancers, while largely leaving the target cancerous tissues unprotected. This protective effect is observed in radiation and chemotherapeutic treatments by, for example, alkylating agents such as cyclophosphamide, cisplatin, carboplatin, doxorubicin and its derivatives, and mitomycin and its derivatives. For representative studies, see, e.g., Constine et al., Int. J. Radia. Oncol. Biol. Phys., 12, 1505-1508 (1986); Liu et al., Cancer, 69(11), 2820-2825 (1992); Wadler et al., J. Clin. Oncol., 11(8), 1511-1516 (1993); and Buntzel et al., Ann. Oncol. 7 (Suppl. 5), 81, 381P (1996).
Similarly, it has been reported that amifostine may be used to protect against the harmful side effects of 3'-azido-3'-deoxythymidine (AZT) therapy. In addition, amifostine and its derivatives appear to exert their protective effects without significantly affecting the beneficial properties of the administered therapeutic agents.
Amifostine is approved in the United States for treatment to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian or non-small cell lung cancer. Physicians' Desk Reference, 51st ed. (1997).
Amifostine is a pro-drug that is dephosphorylated at the tissue site by alkaline phosphatase to the free thiol, which is the active metabolite (WR-1065). Without wishing to be bound by theory, it is believed that once inside the cell, the active free thiol can protect against the toxicities associated with radiation by acting as a scavenger for oxygen free-radicals (See, Yuhas in Radiation-Drug Interactions in Cancer Management pp. 303-352 (1977), Yuhas, J. Natl. Cancer Inst., 50, 69-78 (1976); Philips et al., Cancer Treat. Rep., 68, 291-302 (1984)).
Amifostine shows these favorable radioprotective effects when administered systemically prior to radiation treatment. Systemic administration, however, suffers from numerous disadvantages. The typical systemic route of administration is intravenously, but administering compounds intravenously is extremely inconvenient, particularly when a daily dosing schedule for several weeks is necessary. In addition, when amifostine is administered systemically, patients suffer from dose-dependent undesirable side-effects such as nausea, vomiting, emesis and hypotension, as well as flushing or feeling of warmth, chills or feeling of coldness, dizziness, somnolence, hiccups and sneezing. At high enough doses, systemic amifostine is toxic.
3.2 Topically Administered Amifostine
Topical administration of amifostine, if feasible, would be advantageous for a number of reasons. The therapeutic effect of radiation is dose-dependent, so that it would be desirable in many cases to increase the radiation dosage, or use an accelerated radiation schedule, in order to increase the cure rate. Such increased doses of radiation, however, require corresponding increases in amifostine doses in order to counteract the damage to normal tissue accompanying the increased or accelerated radiation schedule. The protective effect of the compound is said to be dependent upon the concentration of amifostine or its active metabolite present in the normal tissue. Because of the adverse side effects of systemic amifostine, however, the amount that can be administered systemically is severely limited. Topical administration would allow greater local control of the amifostine concentration, allowing higher local concentrations without delivery of the higher doses to unaffected tissues and organs. To date, however, topical administration of amifostine has not been shown to be feasible.
The need for an effective topical radiation and chemotherapy ("radio/chemo") protectant is especially acute in patients suffering from radiation or chemically induced damage to mucosal tissue, such as mucositis and conditions associated with mucositis. As a specific example, cancers of the head and neck are often highly localized, and would benefit from aggressive radio/chemo treatment The normal mucosal tissues of the bead and neck region, such as the oral mucosa, are susceptible to chemical and radiation damage. Chemical, radiation, and combined radiation and chemical treatment act to deplete the mucosal basal epithelium, thinning the tissue and causing inflammation, swelling, erythema and ultimately ulceration.
Ulceration of the mucosa leads to additional complications, as the exposed underlying tissue is vulnerable to infection. For example, Bourhis et al. evaluated an accelerated radiation schedule in patients suffering from locally advanced head and neck cancers. Bourhis et al., Int. J. Radiat. Oncol. Biol. Phys., 32(3), 747-752 (1995). In all of the patients treated with the accelerated schedule, confluent mucositis was observed, and more than half of the patients required hospitalization to treat the mucositis. Similar results were reported by Delaney et al. (96% showed confluent mucositis), following a different aggressive radiotherapy schedule. Delaney et al., Int. J. Radiat. Oncol. Biol. Phys., 32(3), 763-768 (1995). But for the sensitivity to head and neck mucosal tissue to radio/chemo damage, more aggressive therapeutic treatments including increased radiation doses and accelerated radiation schedules could be particularly effective at treating cancers in these regions. Thus, protection of mucosal tissue of the head and neck regions would be especially advantageous.
3.2.1 Topical Application to Non-Mucosal Tissue
Although much is known about the radioprotective effects of systemically administered amifostine and related compounds, relatively little is known about the effects of these compounds when administered topically. The few studies which have addressed topical administration have produced inconclusive results.
In an early study, Utley et al. found that topical administration of amifostine in carbowax to the oral mucosa of mice subjected to whole head irradiation prevented oral radiation death syndrome (LD50/8-10) by a factor of 1.4, with no toxicity observed at the dosages tested. Utley et al., Int. J. Radiat. Oncol. Biol. Phys., 1, Supp. 1, No. 154 (1976). Systemically administered amifostine was found to be more effective in preventing oral radiation death, although some deaths due to drug toxicity were reported. The study did not address protection of other tissues or of the oral mucosa per se from mucositis.
Several studies have looked at the radioprotective effects of topical amifostine on radiation-induced damage to non-mucosal tissue, particularly to rat and mouse skin.
In an early pre-clinical study, Lowy et al. studied the radioprotective effects of systemically and topically administered amifostine in mice. Lowy et al., Radiation Biology, 105, 425-428 (1972). The amifostine was administered to mouse skin as a paste formed from an aqueous sodium bicarbonate solution (pH 7) and Unibase. Although the study found systemically administered amifostine to be effective in reducing the severity of radiation damage, topically applied amifostine was found to provide no radioprotective effect at any dose studied.
Similarly, Verhey et al. found amifostine to be ineffective to protect mouse skin from radiation-induced damage when applied topically. Verhey et al., Radiation Research, 93, 175-183 (1983). A gauze saturated with a 10% solution of amifostine in saline was applied to murine skin for 15 to 60 minutes, followed by .sup.137 Cs irradiation. The study found no significant radioprotective effects for topically-applied amifostine.
More recently, Geng et al. compared the effects of topically and systemically administered 16,16 dm prostaglandin E.sub.2 (PGE.sub.2) and amifostine on radiation-induced alopecia in mice. Gong et al., Int. J. Radial. Biol., 61(4), 533-537 (1992); see also Malkinson et al., J. Invest. Dermatol., 101 (suppl), 135S-137S (1993), reporting similar results. In the topical studies, a 0.3 mg sample of the dephosphorylated form of amifostine, WR-1065, in 0.2 mL Ringer's solution was administered to the depilated mouse skin prior to fractionated irradiation treatment, then the rate of hair regrowth was studied as a function of radiation dosage. Although topically administered WR-1065 showed some effectiveness in protecting hair matrix cells from radiation-induced injury, the Geng study found systemically administered amifostine to be more effective at all radiation doses studied.
3.2.2 Topical Application to Mucosal Tissue
Several studies have examined the possibility of using amifostine or related compounds topically to protect intestinal mucosal tissue from radiation damage.
Ben-Josef et al. demonstrated that amifostine applied topically by an intrarectal injection of a 2% amifostine gel results in an accumulation of the amifostine metabolite WR-1065 in the rectal wall of rats. Ben-Josef et al., Radiation Research, 143, 107-110 (1995). The study did not, however, examine the radioprotective effect in mucosal tissue that might result from the accumulated WR-1065.
Montana et al. tested the effect of amifostine applied topically to protect intestinal mucosa in patients undergoing radiation treatment of the pelvis. Cancer, 69(11), 2826-2830 (1992). An amifostine in Proctofoam preparation was administered topically by enema at dosages of 100 to 450 mg per enema 45 minutes prior to pelvic radiation treatment. The Montana et al. study found that topically applied amifostine avoided many of the side effects typically observed when the drug is administered systemically. However, no significant differences were found in rectal mucosal damage between a control group, which did not receive amifostine, and a test group, which received the topical amifostine treatments. Montana et al. speculated that the lack of protective effect may be due to the mode of administering the drug.
An opposite conclusion was reached in an animal study by Delaney et al. Delaney et al., Cancer, 74(8), 2379-2384 (1994). Delaney et al. studied the radioprotective effect of topical solutions of amifostine injected into the small intestine of rats. Amifostine was prepared in a pH 9 Tris buffer (tris(hydroxymethyl)aminomethane) at a concentration of 150 mg/mL, and administered intralumenally prior to irradiation of the exteriorized rat small bowel. The study concluded that amifostine, and particularly amifostine in an alkaline vehicle, was an effective radioprotector against intestinal mucositis in rats.
Clearly, the results of these limited studies have been inconclusive and can be considered contradictory. There is some evidence that topical amifostine or WR-1065 may provide protection of skin or intestinal mucosa, but the studies to date show conflicting results. In addition, the studies of mucosal tissues to date have focused on intestinal mucosa and the effects of radiation induced mucosal tissue damage that accompanies pelvic irradiation. Some studies suggest that the vehicle used to deliver the active agent may be a factor to consider in determining potential efficacy.
Mucosal tissues of the head and neck region are particularly sensitive to radiation and chemically-induced damage association with radiochemical treatment of head and neck cancers. Mucositis of these tissues results in extreme patient discomfort, as well as in complications due to infection of ulcerated mucositic tissues. There has yet to be identified a safe and effective method of protecting the mucosal tissues of the head and neck region from radiochemically-induced damage without the undesirable side effects of systemic administration of protectant drugs.
Thus, there is a need for a safe and effective method of protecting tissues from damage due to radio- or chemotherapeutic treatments while avoiding the undesirable effects of systemically administered radio/chemo protectants.